The Next Generation: Retatrutide, CagriSema, and What's Coming

If you think today's GLP-1 medications are impressive, the pipeline is even more exciting. Drugs showing 25-29% weight loss. Triple agonists targeting three hormone receptors. Oral options at reasonable prices. Medications specifically designed for liver disease.

This article surveys what's coming—the drugs in late-stage development that will reshape weight loss treatment over the next few years.

The Current Landscape: Where We Are

Before looking ahead, here's what's available now (January 2026):

Medication	Weight Loss	Mechanism	Status
Wegovy (semaglutide 2.4mg)	~15%	GLP-1 only	FDA approved
Zepbound (tirzepatide 15mg)	~21%	GLP-1 + GIP dual	FDA approved
Oral Wegovy (semaglutide 25mg)	~16%	GLP-1 only	FDA approved Dec 2025

These represent the first and second generations. What comes next pushes even further—targeting additional hormones, achieving greater efficacy, and addressing specific conditions.

Retatrutide: The Triple Agonist Leader

If tirzepatide's dual mechanism was a breakthrough, retatrutide takes it further with three hormone targets.

What the Glucagon Component Adds

Glucagon is typically thought of as the "opposite" of insulin—raising blood sugar. So why add it to a weight loss drug?

• Increased energy expenditure: Glucagon increases metabolic rate, burning more calories at rest
• Enhanced fat burning: Mobilizes fat from storage for energy
• Liver effects: May improve fatty liver disease more effectively
• Appetite suppression: Glucagon has independent satiety effects

The concern: glucagon raises blood sugar. But in the triple agonist, the GLP-1 and GIP components counterbalance this, maintaining glucose control while capturing the metabolic benefits.

The TRIUMPH-4 Results

The phase 3 TRIUMPH-4 trial in patients with obesity and knee osteoarthritis showed:

• 28.7% weight loss at the 12mg dose over 68 weeks
• 75.8% improvement in osteoarthritis pain scores (WOMAC)
• Many patients achieved 30%+ weight loss—approaching surgical outcomes

The osteoarthritis improvements were striking: weight loss combined with direct anti-inflammatory effects produced dramatic pain relief.

CagriSema: Semaglutide Plus Amylin

Novo Nordisk isn't standing still. CagriSema combines semaglutide with cagrilintide, an amylin analog.

What Amylin Adds

Amylin is a hormone co-secreted with insulin from pancreatic beta cells. Its effects:

• Slows gastric emptying (complementing GLP-1)
• Suppresses glucagon after meals
• Acts on the brain to reduce appetite through different pathways than GLP-1
• May have additive satiety effects when combined with GLP-1

The REDEFINE 1 trial showed CagriSema significantly outperformed semaglutide alone: 22.7% versus 16.1% weight loss. More than half of CagriSema users achieved ≥20% loss compared to just 16.2% with semaglutide monotherapy.

CagriSema is essentially "enhanced Wegovy"—for people who respond to semaglutide but want more, this could be the upgrade path.

Survodutide: The MASH Specialist

Boehringer Ingelheim's survodutide is a GLP-1/glucagon dual agonist with particularly impressive liver disease data.

The 62% MASH resolution rate versus 14% with placebo is remarkable. For the millions with fatty liver disease progressing toward cirrhosis, this could be transformative. Phase 3 results expected H1 2026.

Amycretin: The Single-Molecule Innovation

Novo Nordisk's amycretin combines GLP-1 and amylin activity in a single molecule—not two drugs combined, but one engineered peptide.

The intriguing finding: no weight loss plateau was observed at study end—participants were still losing. This suggests potential for even greater efficacy with longer treatment. The oral formulation achieved 13.1% loss in just 12 weeks—faster than current oral options.

Oral Wegovy: Already Here

One "pipeline" drug has already arrived. Oral semaglutide 25mg for weight management was FDA-approved in December 2025.

Key considerations:

• Slightly lower efficacy: 16.6% versus injectable's ~17%, likely due to absorption variability
• Dramatically lower price: $299/month versus $1,349 for injectable—a major accessibility improvement
• No injection required: Removes a barrier for needle-averse patients
• Specific dosing requirements: Take on empty stomach with small water amount; wait 30 minutes before eating

For many people, the slight efficacy trade-off is worth the convenience and cost savings.

When Will These Be Available?

Timelines can shift—regulatory decisions, manufacturing challenges, and trial results all affect approval dates. But the trajectory is clear: more options, better efficacy, multiple mechanisms.

How Do They Compare?

Drug	Mechanism	Weight Loss	Unique Advantage
Wegovy	GLP-1	~15-17%	Proven CV benefit; oral option
Zepbound	GLP-1 + GIP	~21%	Best current efficacy; better muscle preservation
Retatrutide	GLP-1 + GIP + Glucagon	~27-29%	Highest weight loss; metabolic boost
CagriSema	GLP-1 + Amylin	~22-23%	Enhanced semaglutide; complementary mechanisms
Survodutide	GLP-1 + Glucagon	~19%	Best liver disease data
Amycretin	GLP-1 + Amylin (single molecule)	22%+ (ongoing)	No plateau observed; oral potential

What This Means for Current Treatment

If you're considering or currently taking GLP-1 medications, what should you make of the pipeline?

If You're Deciding Whether to Start

Don't wait. Today's medications work. Waiting for "something better" means losing years of health benefits. You can always switch later if superior options emerge.

If You're Currently on Semaglutide and Satisfied

Continue your current treatment. The pipeline may offer upgrades, but semaglutide has the longest safety record and proven cardiovascular benefits.

If You've Plateaued or Want Better Results

Tirzepatide is available now with better efficacy. By 2027, retatrutide may offer even more. Planning with your provider for potential medication changes makes sense.

If Cost Is a Major Barrier

Oral Wegovy at $299/month is dramatically more accessible than injectable options. As competition increases, prices should continue falling across the category.

The Broader Picture: Competition and Access

The pipeline isn't just about efficacy—it's about competition. More drugs means:

• Lower prices: Competition drives costs down
• Reduced shortages: Multiple manufacturers improve supply
• More insurance coverage: As medications become standard of care, coverage expands
• Tailored options: Different drugs for different patient profiles

By 2030, the weight management medication landscape will be unrecognizable compared to even 2024. Multiple highly effective options, oral formulations, combination therapies, and (eventually) generics will transform access.